An Hypothesis Concerning the Role of Carnitine in the Control of Interrelations between Fatty Acid and Carbohydrate Metabolism

AN HYPOTHESIS CONCERNING THE ROLE OF CARNITINE IN THE CONTROL OF INTERRELATIONS BETWEEN FATTY ACID AND CARBOHYDRATE METABOLISM IRVING B. FRITZ* I. Preface: Suggestions to the Reader When I initially submitted this article to Perspectives, I was aware that the manuscript was a little schizophrenic. On the one hand, it was an effort to introduce some ideas about the biology of metabolic regulation and to offer the notion that carnitine played an important role as a potential regulator. On the other hand, the manuscript contained a fair amount of rather technical material which was likely to be of interest chiefly to specialists, thereby failing to fulfil a prerequisite for articles in Perspectives to be within the purview ofgeneral readers. In musing over the difficulty, I realized that I could sketchily provide essential background information in amountsjust sufficient to define the problem in its proper context and then tell the carnitine story. But I was unhappy with prospects ofdeleting details because I felt that speculations advanced could not be adequately evaluated in the absence of biochemical documentation. In response to this dilemma, which was brilliantly delineated by two anonymous but highly articulate reviewers to whom I am indebted, I hit upon the following method of handling the revised manuscript: instead of trying to cure the schizophrenia, I would recognize it! A reorganization has ensued such that the body ofthe paper contains material ofgeneral interest. Hopefully, the reader ofPerspectives who is not a biochemist , but who is interested in the biological aspects of metabolic control, will not be unduly handicapped in reading all sections up to * Department ofPhysiology, University ofMichigan, Ann Arbor. Research from this laboratory was supported by NIH grant AM-01465, U.S. Public Health Service. It is a pleasure to acknowledge my indebtedness to colleagues and co-workers for many stimulating discussions which helped greatly in the formulation and expression ofmaterial presented. I am particularly grateful to Reed Detar for his excellent criticisms and suggestions. 643 the last one. In contrast, the Appendix is for the biochemically oriented reader who would like to have before him a more traditionally documented review ofevidence marshaled in support ofideas presented. For the reader who has still less desire to examine biochemical pathways , it is possible to gain the major points ofbiological interest by proceeding directly from section II to section IV, pausing only to scan figures and schema. II. Statement ofthe Problem and the Hypothesis During times of food deprivation, hepatic metabolism is dramatically altered. Complex pathways exist which permit the organism to synthesize large amounts offat when food is plentiful and appetite is voracious. On the other hand, when food is scarce or appetite is reduced, regulatory systems exist which rapidly decrease net fat and protein synthesis and which simultaneously increase both hepatic and renal glucose production. From a functional viewpoint, these systems act to provide a steady supply of glucose to the nervous system during times of uncertain food supply. The responsible mechanisms which have evolved are clearly of survival value in permitting an animal to sustain itself between successful hunts for nourishment. The comparative aspects of these problems have been dealt with in part by Drabkin [i], to whom the reader is referred for a provocative discussion ofmetabolic homeostasis. A signal exists for changing metabolic pathways in the liver from one of net fat synthesis to one of net glucose and ketone body production. The signal, obscure though it is, appears to be closely associated with a decreased rate ofglucose utilization by peripheral tissues and an increased rate offatty acid oxidation. These changes in the pathways ofmetabolism, which may be triggered by starvation, by insulin deficiency, or by fat administration, are part of a larger metabolic pattern summarized in Figure i. It is characteristic that as fatty acid oxidation and ketone body formation increase, the rate of glucose production (gluconeogenesis) by liver and kidney also increases , but the rate of fatty acid synthesis decreases. The central role of lipid mobilization and plasma fatty acid levels in this scheme should be noted. Decreased glucose utilization and increased fatty acid oxidation may well be a consequence of an increased mobilization of fat from adipose tissue. As shown at the top of...